11

ALI/ARDS IN SEPSISALI/ARDS IN SEPSIS

Dr Gül GürselDr Gül GürselGazi University School of Gazi University School of Medicine Department of Medicine Department of

Pulmonary DiseasesPulmonary Diseases

22

60% of etiologies in ALI are sepsis60% of etiologies in ALI are sepsisPulmonary source 46%, other source 33%Pulmonary source 46%, other source 33%11

KCLIPKCLIP11

ScandinaviScandinaviaa22

AustraliAustraliaa33

ALI incidenceALI incidence

Cases per Cases per 100000 100000 person-yearperson-year

78.978.9 17.917.9 3434

Mortality Mortality from ALIfrom ALI

38.538.5 41.441.4 3232

1 NEJM 2005; 353:1685-93(King County Lung Injury Project-KCLIP)2 Am J Respir Crit Care Med 1999; 159:1849-613 Am J Respir Crit Care Med 2000; 165:443-8

33

The American-European consensus The American-European consensus conference criteria for ALI and ARDSconference criteria for ALI and ARDS

ALIALI Acute onset PaO2/FiO2300

mmHg(regardless of PEEP level)

Bilateral infiltrates PAOP 18 mmHg or no

clinical evidence of left atrial hypertension

ARDSARDS• Acute onset• PaO2/FiO2200

mmHg(regardless of PEEP level)

• Bilateral infiltrates• PAOP 18 mmHg or no

clinical evidence of left atrial hypertension

Am J Resp Crit Care Med 1994;149:818-824

44

Edema fluid to plasma protein concentrations <0.65 transudate in hydrostatic pulmonary edema>0.65 exudate in increased permeability pulmonary edema(ALI/ARDS)

Matthay MA et al Physiol Rev 2002; 82:569-600

55

Clinical disorders associated with the development of ALI and ARDS

DİRECT LUNG INJURY(PULMONARY) Aspiration of gastric

contents Pneumonia Near drowning Inhalational injuries Pulmonary contusion Pulmonary embolic

disorders Reperfusion injury Thoracic radiotherapy

INDIRECT LUNG INJURY(EXTRAPULMONARY) Sepsis, SIRS Severe trauma with shock Acute pancreatitis Transfusion of blood

products Drug overdose and toxins Anaphylaxis ECMO, CAGS Decompression sickness

66

Type I(90%), Type I(90%), Type II(10%) alveolar Type II(10%) alveolar

epitelial cellsepitelial cells Capillary endothelial cellsCapillary endothelial cells İnterstitiumİnterstitium

77

Problems in ALIProblems in ALI

ALI=edema+inflammationALI=edema+inflammation Leukocyte recruitment and/or activationLeukocyte recruitment and/or activation Alveolar epitheal cell damage/alterationAlveolar epitheal cell damage/alteration Lung surfactant dysfunction/inactivationLung surfactant dysfunction/inactivation Pulmonary interstitial injuryPulmonary interstitial injury Inflammatory mediators/factors producedInflammatory mediators/factors produced Microvascular dysfunctionMicrovascular dysfunction Airway injuryAirway injury Coagulation abnormalitiesCoagulation abnormalities

88

NEJM 2000 ;342 :1334-48

99

Resident and Recruited Cells of The Lung Inflammatory Response

Cell typeCell type Chemotactic and activating Chemotactic and activating mediatorsmediators

Role in Role in inflammationinflammation

NeutrophilsNeutrophils Bacterial products, Bacterial products, TNFTNF,IL8,GM-CSF,,IL8,GM-CSF,IFN,C5a, IFN,C5a, LTB4,endothelial adhesion LTB4,endothelial adhesion moleculesmolecules

Phygocytosis; Phygocytosis; production of production of oxidants, oxidants, proteinases, proteinases, defensinsdefensins

Monocytes/Monocytes/

MacrophagMacrophageses

MCP-1, MIP-1 MCP-1, MIP-1 ,IFN- ,IFN- , TNF , TNF, , IL- 1 IL- 1

production of production of oxidants, NO, oxidants, NO, proteinases,proteinases,

““Walling off “ insult Walling off “ insult (granuloma)(granuloma)

LymphocytLymphocyteses

IL-2, IL12, IFN- IL-2, IL12, IFN- , IL-4, IL-10, IL-4, IL-10 Release of cytoxins Release of cytoxins that injure cells, that injure cells, release of proformed release of proformed antibodies to forign antibodies to forign substancesubstance

PlateletsPlatelets IL-1 IL-1 , HMBG, chemokines, HMBG, chemokines

Sphingosine-1 phosphateSphingosine-1 phosphateOrganise fibrin clotsOrganise fibrin clots

Promotes endothelial Promotes endothelial barier barier function(repair)?function(repair)?

1010

Resident and Recruited Cells of The Lung Inflammatory Response

Cell typeCell type Chemotactic and Chemotactic and activating mediatorsactivating mediators

Role in inflammationRole in inflammation

EosinophilEosinophil Rantes, MIP-1 Rantes, MIP-1 ,eotaxin, histamine,eotaxin, histamine

Release of oxidants and Release of oxidants and cationic proteins; airway cationic proteins; airway reactivityreactivity

BasophilsBasophils MCP-1MCP-1 Major source of vasoactive Major source of vasoactive aminesamines

Endothelial Endothelial cellscells

TNFTNF, IL- 1 , IL- 1 , oxidants, oxidants Generation of Generation of oxidants;increase of leakiness oxidants;increase of leakiness for leokocyte infiltration and for leokocyte infiltration and other blood borne mediatorsother blood borne mediators

Epithelial Epithelial cellscells

TNFTNF, IL- 1 , IL- 1 , oxidants, oxidants Generation of oxidants, Generation of oxidants, surfactant;barier function to surfactant;barier function to protect systemprotect system

FibroblastsFibroblasts TNFTNF, IL- 1 , IL- 1 , oxidants, , oxidants, FGF, TGF FGF, TGF

Generation of Generation of oxidants;”walling off” oxidants;”walling off” insult;initial repeir to insult;initial repeir to structural damage structural damage

1111

Soluble mediators of Soluble mediators of inflammationinflammationMediatorsMediators Major sourceMajor source İnflammatory roleİnflammatory role

Vazoactive Vazoactive peptidespeptides

Mast cells, Mast cells, basophils, pltbasophils, plt

Vasodilatation, increased vascular Vasodilatation, increased vascular permeabilitypermeability

ComplemeComplementnt

Liver(9),mono,MALiver(9),mono,MA, fibroblast, fibroblast

Augmented phagocytosis, increased Augmented phagocytosis, increased vascular permeability, chemotaxisvascular permeability, chemotaxis

KininsKinins Soluble forms in Soluble forms in bloodblood

Vasoconstriction, increased vascular Vasoconstriction, increased vascular permeability, chemotaxispermeability, chemotaxis

Fibrinolytic Fibrinolytic peptidespeptides

Proteolytic Proteolytic clevage of fibrinclevage of fibrin

Activaion of C and FXIIActivaion of C and FXII

PGsPGs Mo,MA, neutro, Mo,MA, neutro, endotelial cell, endotelial cell, pltplt

İncreased body temp, stim f İncreased body temp, stim f nociceptorsincreased vascular nociceptorsincreased vascular permeabilitypermeability

LTsLTs Lc with Lc with methabolic methabolic conversionconversion

Vasoconstriction, increased vascular Vasoconstriction, increased vascular permeability,neutrophil rec and permeability,neutrophil rec and activationactivation

PAFPAF Plt, Lc, Plt, Lc, endotheial cellendotheial cell

Plt aggregation, leucocyte rec and Plt aggregation, leucocyte rec and activationactivation

CytokinesCytokines Lc and structural Lc and structural cellscells

Recruit and activate leucocytes, Recruit and activate leucocytes, augment, modulate and resolve the augment, modulate and resolve the inflam responseinflam response

1212

Soluble Chemical Effectors of Soluble Chemical Effectors of InflammationInflammation

EffectorsEffectors SourceSource Inflammatory Inflammatory functionfunction

Negative effectsNegative effects

OxidantsOxidants Lc, Enc, Lc, Enc, EpcEpc

Kill microbes and Kill microbes and cells harbouring cells harbouring microbesmicrobes

Dmamage proteins, Dmamage proteins, lipids, and nuc acids, lipids, and nuc acids, cell death,inactivate cell death,inactivate antiproteinasesantiproteinases

ProteinasesProteinases All cells All cells followed followed injuryinjury

Activate the Activate the inflammatory inflammatory responseresponse

Damage connective Damage connective tissue,cell tissue,cell membranes, membranes, inactivate inactivate antiaxidantsantiaxidants

NONO Enc,Mo/Enc,Mo/MacMac

VasorelaxationVasorelaxation May generate highly May generate highly toxic reactive toxic reactive nitrogennitrogen

AntioxidantsAntioxidants All cellsAll cells Terminate oxidant Terminate oxidant activityactivity

AntiproteasisAntiproteasis All cellsAll cells Terminate proteinase Terminate proteinase activityactivity

1313

The role of Toll-like The role of Toll-like receptors(TLRs) in pulmonary host receptors(TLRs) in pulmonary host

responseresponse

TLR are the first to detect host TLR are the first to detect host invasion by pathogens, initiate invasion by pathogens, initiate immune responses and form the immune responses and form the crucial link between the innate and crucial link between the innate and adaptive immune systemsadaptive immune systems

1414

The role of Toll-like receptors(TLRs) in The role of Toll-like receptors(TLRs) in pulmonary host responsepulmonary host response

TLR4 recognizes LPS of gram-negative TLR4 recognizes LPS of gram-negative bacteria and subsequently induces an bacteria and subsequently induces an inflammatory responseinflammatory response

Gram-positive PAPMs are all ligans of TLR2Gram-positive PAPMs are all ligans of TLR2 Lipoteichoic acidLipoteichoic acid LipoproteinsLipoproteins peptidoglycanpeptidoglycan

SHOCK 2005; 24:12-18

1515

1616

1717NEJM 2004; 351:853-855

Role of Surfactant in ALIRole of Surfactant in ALI

1818

1919

Endogenous compouns that Endogenous compouns that inhibit lung surfactant activityinhibit lung surfactant activity

Biophysical inhibitorsBiophysical inhibitors Plasma en blood proteins(alb, Hb, fibrinogen)Plasma en blood proteins(alb, Hb, fibrinogen) Cell membrane lipidsCell membrane lipids LysophospholipidsLysophospholipids Fluid free fatty acidsFluid free fatty acids Glycolipids and sphingolipidsGlycolipids and sphingolipids

Chemically acting inhibitorsChemically acting inhibitors Lytic enzymes(proteases, phospholipases)Lytic enzymes(proteases, phospholipases) Reactive oxygen and nitrogen speciesReactive oxygen and nitrogen species Antibodies to surfactant proteinsAntibodies to surfactant proteins

2020Am J Respir Cell Moll Biol 2005; 33:319-327

2121Am J Respir Cell Moll Biol 2005; 33:319-327

2222

2323

ApoptosisApoptosis

Neutrophil apoptosis is inhibited early in Neutrophil apoptosis is inhibited early in ARDS and that the lifespan of neutrophils ARDS and that the lifespan of neutrophils returns to normal as inflammation returns to normal as inflammation resolvesresolves

Apoptosis of alveolar epithelial cells by Apoptosis of alveolar epithelial cells by the Fas/Fas ligand system may also be of the Fas/Fas ligand system may also be of particular importance in the development particular importance in the development of the permeability changesof the permeability changes

Critical Care 2003; 7: 355-8

2424

2525

Am J Respir Cell Moll Biol 2005; 33:319-327Mutlu G, Am J Respir Crit Care Med 2004;170:1270-1275

2626

2727

The influence of preexisting The influence of preexisting inflammationinflammation

During severe inflammation such as sepsis During severe inflammation such as sepsis immune response follows a biphasic patternimmune response follows a biphasic pattern

Overwhelming proinflammatory response leads Overwhelming proinflammatory response leads to tissue injuryto tissue injury

Excessive activation of antiinflammatory Excessive activation of antiinflammatory pathways results in impaired pulmonary host pathways results in impaired pulmonary host defencedefence Dysfunctional mononuclear cellsDysfunctional mononuclear cells Apoptosis of immune cellsApoptosis of immune cells Production of anti-inflammatory cytokines such as IL-Production of anti-inflammatory cytokines such as IL-

1010

2828

Local pulmonary host defense during Local pulmonary host defense during respiratory tract infections is respiratory tract infections is influenced by sepsis or sepsis like influenced by sepsis or sepsis like sydromessydromes

J Immunol 1999; 162:392-399J Immunol 1999; 162:392-399 J Immunol 2000; 165:6496-6503J Immunol 2000; 165:6496-6503 Shock 2004; 21:415-425Shock 2004; 21:415-425

Incidence of VAP in ARDS =60%Incidence of VAP in ARDS =60% Am J Respir Crit Care Med 1997;156:1092-8Am J Respir Crit Care Med 1997;156:1092-8

2929

JAMA 1999;282:54-61

3030

J Pathol 2004; 203:631-7

3131

Angiotensin-converting enzyme and Angiotensin-converting enzyme and ALIALI

Angiotensin-converting enzyme(ACE) has Angiotensin-converting enzyme(ACE) has been identified as the functional receptor for been identified as the functional receptor for SARS-CoVSARS-CoV

Wenhui Li NATURE 2003; 426:450-454Wenhui Li NATURE 2003; 426:450-454

Mice deficient for ACE showed markedly Mice deficient for ACE showed markedly improved disease and recombinant ACE2 improved disease and recombinant ACE2 can protect mice from severe acute lung can protect mice from severe acute lung injuryinjury

NATURE 2005;436:112-6NATURE 2005;436:112-6 ACE polymorfism is a significant prognostic ACE polymorfism is a significant prognostic

factor for the outcome of ARDSfactor for the outcome of ARDS Crit Care Med 2006;34:1001-6Crit Care Med 2006;34:1001-6

3232

Crit Care Med 2006;34:1001-6Crit Care Med 2006;34:1001-6